Tripeptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) Regulate the Proliferation and Migration of Vascular Smooth Muscle Cells by Interfering Ang II-Induced Human Umbilical Vein Endothelial Cells Derived EVs Delivering RNAs to VSMCs in the Co-culture Model

Abstract

Angiotensin II (Ang II), a vasoactive factor in the renin−angiotensin−aldosterone system (RAAS), can regulate vasoconstriction and promote multiple vascular diseases. In this study, the effects of potent antihypertensive peptide Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) on the proliferation and migration of vascular smooth muscle cells (VSMCs) by extracellular vesicles (EVs) from vascular endothelial cells (VECs) were studied using a cell co-culture model. The VEC-derived EVs were isolated, characterized, and investigated. The present study demonstrated that the EVs from Ang II-induced VECs could promote proliferation, migration, and inflammatory factors (IL-6 increased to 40.75 ± 4.33 pg/mL and IL-1β increased to 28.62 ± 5.42 pg/ mL) generation of VSMCs, VPP and IPP exerted discrepant inhibitory effects on this pathway. The EVs with RNase treatment lost the effects on VSMCs, indicating that the RNAs packed into vesicles may be a critical component. These results implied that VPP and IPP could alleviate Ang II-induced vascular dysfunction by modulating the EV-mediated transmission of RNAs between VECs and VSMCs.

Soybean-Derived Antihypertensive Peptide LSW (Leu–Ser–Trp) Antagonizes the Damage of Angiotensin II to Vascular Endothelial Cells through the Trans-vesicular Pathway

“…Importantly, the antagonistic effect of tripeptide LSW on Ang II could be extended by this signal medium. Based on previous research in our laboratory, , we had sufficient evidence to speculate that the extracellular vesicles (EVs) might be responsible for this process.…”

“…EVs have been recognized as an important bridge between VSMCs and VECs to maintain vascular homeostasis by transferring nucleic acids, proteins, and lipids . Recently, our lab has verified that Ang II, being an endogenous octapeptide, can convert the function of vascular cell-derived EVs; foremost, the EVs from Ang II-induced VSMCs or VECs could promote inflammatory and endothelial dysfunction in the recipient cells. , In this study, we tried to analyze the transcriptional differences of the two kinds of EVs from VSMCs with Ang II incubation, which has the effect of contracting blood vessels, and tripeptide LSW, which has the effect of improving the proliferation of VSMCs.…”

“…The VSMCs with or without LSW/Ang II incubation were cultured in DMEM media containing 10% FBS until the confluence was over 80%, the original growth media was abandoned, and then the phosphate buffer was used to softly wash the cells three times. The fresh serum-free media was added and kept to culture for 48 h. The detailed isolation protocol could be referred to our previously published study . A protein quantitative analysis was performed to detect the protein concentration of EVs.…”

A Novel Angiotensin I-Converting Enzyme Inhibitory Peptide Derived From Goat Milk Casein Hydrolysate Modulates Angiotensin II-Stimulated Effects on Vascular Smooth Muscle Cells

“…Due to the important role of ACE in hydrolyzing angiotensin I into angiotensin II under the condition of strong vasoconstriction, ACE-inhibition has always been a key target of anti-hypertensive research ( 43 , 44 ). It has been stated that ACE-inhibitory peptides have a variety of blood pressure-lowering effects other than ACE inhibition ( 8 ).…”

“…Dysfunction of VSMCs can be induced by Ang II and results in adverse events like increased oxidative stress, inflammation, migration, and hyperplasia, and therefore plays a key role in the pathogenesis of hypertension, restenosis, and atherosclerosis ( 46 , 47 ). The pathological proliferation and migration of VSMCs induced by Ang II are the dominative factor of vascular remodeling ( 43 ). Studies have found that antihypertensive peptides derived from egg white can inhibit migration and regulate Ang II-stimulated VSMCs ( 48 , 49 ).…”